This invention relates to a series of substituted pyrazoles, pharmaceutical compositions containing these compounds, and intermediates used in their manufacture, and methods of using them.
Cathepsin S (EC 3.4.22.27) is a cysteine protease of the papain family found primarily in lysosomes (Bromme, D.; McGrath, M. E. High Level Expression and Crystallization of Recombinant Human Cathepsin S. Protein Science 1996, 5, 789-791).
The role of cathepsin S in the immune response is anticipated by its tissue distribution: cathepsin S is found primarily in lymphatic tissues, lymph nodes, the spleen, B lymphocytes, and macrophages (Kirschke, H. Chapter 211. Cathepsin S. In Handbook of Proteolytic Enzymes. Barrett, A. J.; Rawlings, N. D.; Woessner, J. F., Eds. San Diego: Academic Press, 1998. pp. 621-624.). Cathepsin S inhibitors have been shown in animal models to modulate antigen presentation and are effective in an animal model of asthma (Riese, R. J.; Mitchell, R. N.; Villadangos, J. A.; Shi, G.-P.; Palmer, J. T.; Karp, E. R.; De Sanctis, G. T.; Ploegh, H. L.; Chapman, H. A. Cathepsin S Activity Regulates Antigen Presentation and Immunity. J. Clin. Invest. 1998, 101, 2351-2363 and Shi, G.-P.; Villadangos, J. A.; Dranoff, G.; Small, C.; Gu, L.; Haley, K. J.; Riese, R.; Ploegh, H. L.; Chapman, H. A. Cathepsin S Required for Normal MHC Class II Peptide Loading and Germinal Center Development. Immunity 1999, 10, 197-206.).
Mice in which the gene encoding cathepsin S has been knocked out are less susceptible to collagen-induced arthritis and their immune systems have an impaired ability to respond to antigens (Nakagawa, T. Y.; Brissette, W. H.; Lira, P. D.; Griffiths, R. J.; Petrushova, N.; Stock, J.; McNeish, J. D.; Eastman, S. E.; Howard, E. D.; Clarke, S. R. M.; Rosloniec, E. F.; Elliott, E. A.; Rudensky, A. Y. Impaired Invariant Chain Degradation and Antigen Presentation and Diminished Collagen-Induced Arthritis in Cathepsin S Null Mice. Immunity 1999, 10, 207-217).
These data demonstrate that compounds that inhibit the proteolytic activity of human cathepsin S should find utility in the treatment of chronic autoimmune diseases including, but not limited to, lupus, rheumatoid arthritis, and asthma; and have potential utility in modulating the immune response to tissue transplantation.
There are a number of cathepsin S inhibitors reported in the literature. The most important patents are listed below.
Certain dipeptidyl nitrites are claimed by Novartis as cathepsin S inhibitors in: Altmann, et. al. WO-99/24460.
Dipeptidyl vinyl sulfones are claimed by Arris (now Axys) as cysteine protease (including cathepsin S) inhibitors in: Palmer, et. al. U.S. Pat. No. 5,976,858.
Certain peptidyl sulfonamides are claimed by Arris/Axys as cysteine protease (including cathepsin S) inhibitors in: Palmer, et. al. U.S. Pat. No. 5,776,718 (assigned to Arris, now Axys) and Klaus, et. al. U.S. Pat. No. 6,030,946 (assigned to Axys).
Compounds somewhat similar to those of the present invention are described in the following references.
Winters, et. al. (Winters, G.; Sala, A.; Barone, D.; Baldoli, E. J. Med. Chem. 1985, 28, 934-940; Singh, P.; Sharma, R. C. Quant. Struct.xe2x80x94Act. Relat. 1990, 9, 29-32; Winters, G.; Sala, A.; Barone, D. in U.S. Pat. No. 4,500,525 (1985)) have described bicyclic pyrazoles of the type shown below. R never contains a heterocyclic ring and no protease inhibitor activity is ascribed to these molecules; they are described as xcex11-adrenergic receptor modulators. 
Shutske, et. al. claim the bicylic pyrazoles below. The pyridine ring is aromatic in their system (Shutske, G. M.; Kapples, K. J.; Tomer, J. D. U.S. Pat. No. 5,264,576 (1993)). Although reference is made to R being a linker to a heterocycle, the claims specify only R=hydrogen. The compounds are referred to as serotonin reuptake inhibitors. 
The compound 2-[4-[4-(3-methyl-5-phenyl-1H-pyrazol-1-yl)butyl]-1-piperazinyl]-pyrimidine is known from EP-382637, which describes pyrimidines having anxiolytic properties. This compound and analogs are further described in EP-502786 as cardiovascular and central nervous system agents. Pharmaceutical formulations with such compounds are disclosed in EP-655248 for use in the treatment of gastric secreation and as anti-ulcer agents. WO-9721439 describes medicaments with such compounds for treating obsessive-compulsive disorders, sleep apnea, sexual dysfunctions, emesis and motion sickness.
The compounds 5-methyl-3-phenyl-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole and 5-bromo-3-(2-chlorophenyl)-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole, in particular the hydrochloride salts thereof, are known from WO-9853940 and CA 122:314528, where these and similar compounds are described as kinase inhibitors in the former reference and possessing affinity for benzodiazepine receptors in the latter reference.
The present invention concerns compounds which can be represented by formula (I): 
wherein:
the dashed line adjacent Cxe2x80x94R6 is absent or an sp2 bond;
Y is nitrogen or R20C;
Z is nitrogen or R21C;
T is nitrogen or R2C;
S is nitrogen or R3C;
xe2x80x83provided between 0 and 3 of S, T, Y, and Z are nitrogen; and further provided that one of S, T, Y, and Z can be xe2x95x90N+xe2x80x94Oxe2x88x92 where the remaining three are not nitrogen;
R20 is selected from hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5alkyl, cyano, nitro, C1-5haloalkyl, RoRpN, RoRpNCxe2x95x90O, C2-8acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C1-5alkylene, phenyl, (phenyl)C1-5alkylene, R14OCxe2x95x90O, R14S, R14SO, and R14SO2;
R21 is selected from hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5alkyl, cyano, nitro, C1-5haloalkyl, RcRdN, RcRdNCxe2x95x90O, C2-8acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C1-5alkylene, phenyl, (phenyl)C1-5alkylene, R15OCxe2x95x90O, R15S, R15SO and R15SO2;
R2 is selected from hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5alkyl, cyano, nitro, C5haloalkyl, ReRfN, ReRfNCxe2x95x90O, C2-8acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C1-5alkylene, phenyl, (phenyl)C1-5alkylene, R16OCxe2x95x90O, R16S, R16SO and R16SO2;
R3 is selected from hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5alkyl, cyano, nitro, C1-5haloalkyl, RgRhN, C2-8acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C1-5alkylene, phenyl, (phenyl)C1-5alkylene, R17OCxe2x95x90O, RmRnNCxe2x95x90O, RmRnNSO2, R17S, R17SO and R17SO2;
R5 and R6 are independently selected from hydrogen and C1-5alkyl;
R7 and R8 independently are hydrogen, C1-5alkyl, C1-5alkenyl, C1-5alkoxy, C1-5alkylthio, halogen, or 4-7 membered carbocyclyl or heterocyclyl; alternatively, R7 and R8 can be taken together to form an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring, which ring may be unsaturated or aromatic; said ring being optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxy, cyano, nitro, amino, Rt, RtOxe2x80x94, RtSxe2x80x94, RtO(C1-5alkylene)-, RtO(Cxe2x95x90O)xe2x80x94, Rt(Cxe2x95x90O)xe2x80x94, Rt(Cxe2x95x90S)xe2x80x94, Rt(Cxe2x95x90O)Oxe2x80x94, RtO(Cxe2x95x90O)(Cxe2x95x90O)xe2x80x94, RtSO2, NHRu(Cxe2x95x90NH)xe2x80x94, NHRuSO2xe2x80x94, and NHRu(Cxe2x95x90O)xe2x80x94;
Rt is C1-6alkyl, phenyl, benzyl, phenethyl, or C2-5heterocyclyl, (C1-5heterocyclyl)C1-6alkylene, NH2, mono- or di(C1-6alkyl)Nxe2x80x94, or R49OR50xe2x80x94, wherein R49 is H, C1-5alkyl, C2-5alkenyl, phenyl, benzyl, phenethyl, C1-5heterocyclyl, or (C1-5heterocyclyl)C1-6alkylene and R50 is C1-5alkylene, phenylene, or divalent C1-5heterocyclyl; and
Ru can be H in addition to the values for Rt;
Rc is hydrogen, C1-5alkyl, phenyl, C2-5heterocyclyl, C2-8acyl, aroyl, R10OCxe2x95x90Oxe2x80x94, RiRjNCxe2x95x90O, R10SOxe2x80x94, R10SO2xe2x80x94, and RiRjNSO2;
Re is hydrogen, C1-5alkyl, phenyl, C2-5heterocyclyl, C2-8acyl, aroyl, R40OCxe2x95x90O, R43R44NCxe2x95x90O, R40SO, R40SO2, and R43R44NSO2;
Rm is hydrogen, C1-5alkyl, phenyl, C2-5heterocyclyl, C2-8acyl, aroyl, R41OCxe2x95x90O, R45R46NCxe2x95x90O, R41SO, R41SO2, and R45R46NSO2;
Ro is hydrogen, C1-5alkyl, phenyl, C2-5heterocyclyl, C2-8acyl, aroyl, R42OCxe2x95x90O, R47R48NCxe2x95x90O, R42SO, R42SO2, and R47R48NSO2;
each of Rd, Rf, Rn, and Rp is independently selected from hydrogen, C1-5alkyl, phenyl, and C2-5heterocyclyl; in addition, Rc and Rd, Re and Rf, Rm and Rn, or Ro and Rp, independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
each of R9, R10, R11, R14, R15, R16, R17, R40, R41, and R42 is independently C1-5alkyl, phenyl, or C2-5heterocyclyl;
each of Ri and Rj, Rk and Rl, R43 and R44, R45 and R46, R47 and R48 are independently hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, or C2-5heterocyclyl; in addition, Ri and Rj, and Rk and Rl, R43 and R44, R45 and R46, and R47 and R48, independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
Rg is hydrogen, C1-5alkyl, phenyl, or C2-5heterocyclyl, C2-8acyl, aroyl, R9OCxe2x95x90O, R18R19NCxe2x95x90O, R9SO, R9SO2, or R18R19NSO2;
Rh is hydrogen, C1-5alkyl, phenyl, or C2-5heterocyclyl; alternatively, Rg and Rh can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
R18 and R19 independently are hydrogen, C1-5alkyl, phenyl, or C2-5heterocyclyl; alternatively, R18 and R19 can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
n is 0, 1 or 2;
G is C3-6alkenediyl or C3-6alkanediyl, optionally substituted with hydroxy, halogen, C1-5alkyl, C1-5alkoxy, oxo, hydroximino, CO2Rk, NRkRl, (L)-C1-4alkylene-, RkRlNCO2, [(L)-C1-5alkylene]amino, N3, or (L)-C1-5alkoxy;
L is amino, mono- or di-C1-5alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, or piperazinyl, wherein available ring nitrogens can be optionally substituted with C1-5alkyl, benzyl, C2-5acyl, C1-5alkylsulfonyl, or C1-5alkoxycarbonyl;
Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with between 1 and 3 substituents independently selected from halogen, C1-5alkoxy, C1-5alkyl, C2-5alkenyl, cyano, azido, nitro, R22R23N, R22S, R22SO, R22SO2, R22OCxe2x95x90O, R22R23NCxe2x95x90O, C1-5haloalkyl, C1-5haloalkoxy, C1-5haloalkylthio, and C1-5alkylthio;
R22 is hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, benzyl, C2-5heterocyclyl, C2-8acyl, aroyl, R11OCxe2x95x90O, R24R25NCxe2x95x90O, R11S, R11SO, R11SO2, or R24R25NSO2;
R23 is hydrogen, C1-5alkyl, phenyl, benzyl, or C2-5heterocyclyl; alternatively, R22 and R23 can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
R24 and R25 are independently hydrogen, C1-5alkyl, phenyl, benzyl, or C1-5heteroaryl; alternatively, R24 and R25 can be taken together to form an optionally substituted 4- to 7-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
R32 is hydrogen, C1-5alkyl, cyano, C1-5hydroxyalkyl, C2-8acyl, xe2x80x94(Cxe2x95x90O)NRvRx, CHO, or C1-6alkoxycarbonyl, wherein each of Rv and Rx is independently selected from H, C1-5alkyl, C1-5hydroxyalkyl, C1-5heterocyclyl, (C1-5heterocyclyl) C1-5alkylene, C1-5aminoalkylene, C3-8acyloxy, CHO, C1-6alkoxycarbonyl, and cyano;
Q is NR33, S, or O;
R33 represents hydrogen, C1-5alkyl, phenyl, benzyl, phenethyl, C2-5heterocyclyl, (C2-5heterocyclyl)C1-5alkylene, C2-8acyl, aroyl, R35OCxe2x95x90O, R36R37NCxe2x95x90O, R35SO, R35S, R35SO2 and R36R37NSO2;
R35 is selected from hydrogen, C1-5alkyl, phenyl, benzyl, phenethyl, and C2-5heteroaryl;
R36 and R37 are each independently selected from hydrogen, C1-5alkyl, phenyl, or C2-5heteroaryl; alternatively, R36 and R37 can be taken together to form an optionally substituted 4- to 7-membered ring heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
wherein each of the above hydrocarbyl or heterocarbyl groups, unless otherwise indicated, and in addition to any specified substituents, is optionally and independently substituted with between 1 and 3 substituents selected from methyl, halomethyl, hydroxymethyl, halo, hydroxy, amino, nitro, cyano, C1-5alkyl, C1-5alkoxy, xe2x80x94COOH, C2-6acyl, [di(C1-4alkyl)amino]C2-5alkylene, [di(C1-4alkyl)amino]C2-5alkyl-NHxe2x80x94COxe2x80x94, and C1-5haloalkoxy;
or a pharmaceutically acceptable salt, amide, or ester thereof; or a stereoisomeric form thereof.
The disclosed compounds are high-affinity inhibitors of the proteolytic activity of human cathepsin S. For use in medicine, the preparation of pharmaceutically acceptable salts of compounds of formula (I) may be desirable.
Certain compounds of the present invention may have one stereogenic atom and may exist as two enantiomers. Certain compounds of the present invention may have two or more stereogenic atoms and may further exist as diastereomers. It is to be understood by those skilled in the art that all such stereoisomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Another aspect of the invention provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. A further embodiment of the invention is a process for making a pharmaceutical composition comprising mixing a disclosed compound as described above, with a suitable pharmaceutically acceptable carrier.
The invention also contemplates pharmaceutical compositions comprising more than one compound of formula (I) and compositions comprising a compound of formula (I) and another pharmaceutically active agent.
The invention features a method of treating disorders or conditions mediated by the cathepsin S enzyme, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. If more than one active agent is administered, the therapeutically effective amount may be a jointly effective amount. The compounds described herein inhibit the protease activity of human cathepsin S, an enzyme involved in the immune response. In preferred embodiments, cathepsin S inhibition is selective. As such, the disclosed compounds and compositions are useful in the prevention, inhibition, or treatment of autoimmune diseases such as lupus, rheumatoid arthritis, and asthma, and for the prevention, inhibition, or treatment of tissue transplant rejection.
Additional features and advantages of the invention will become apparent from the detailed description below, including examples, and the appended claims.
The invention features pyrazole compounds of formula (I), methods of making them, compositions containing them, and methods of using them to treat diseases and conditions, including those mediated by Cathepsin S.
A. Terms
The following terms are defined below and by their usage throughout this disclosure.
xe2x80x9cAlkylxe2x80x9d includes optionally substituted straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on. Alkyl includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
xe2x80x9cAlkenylxe2x80x9d includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbonxe2x80x94carbon double bond (sp2). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkenyl includes cycloalkenyl. Cis and trans or (E) and (Z) forms are included within the invention.
xe2x80x9cAlkynylxe2x80x9d includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbonxe2x80x94carbon triple bond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl does not include cycloalkynyl.
xe2x80x9cAlkoxyxe2x80x9d includes an optionally substituted straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on. xe2x80x9cAminoalkylxe2x80x9d, xe2x80x9cthioalkylxe2x80x9d, and xe2x80x9csulfonylalkylxe2x80x9d are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO2. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, and so on.
xe2x80x9cArylxe2x80x9d includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, and so on, any of which may be optionally substituted. Aryl also includes arylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Aryl includes a ring system containing an optionally substituted 6-membered carbocyclic aromatic ring, said system may be bicyclic, bridge, and/or fused. The system may include rings that are aromatic, or partially or completely saturated. Examples of ring systems include indenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.
xe2x80x9cHeterocyclylxe2x80x9d includes optionally substituted aromatic and nonaromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom moiety (SO2, CO, CONH, COO) in the ring. Unless otherwise indicated, a heterocyclic radical may have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or 1-pyrazolyl. Preferably a monocyclic heterocyclyl has between 4 and 7 ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5heteroatoms or heteroatom moieties in the ring, and preferably between 1 and 3. A heterocyclyl may be saturated, unsaturated, aromatic (e.g., heteroaryl), nonaromatic, or fused.
Heterocyclyl also includes fused, e.g., bicyclic, rings, such as those optionally condensed with an optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring. For example, xe2x80x9cheteroarylxe2x80x9d includes an optionally substituted six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms condensed with an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring. Said heterocyclic five- or six-membered aromatic ring condensed with the said five- or six-membered aromatic ring may contain 1, 2 or 3 nitrogen atoms where it is a six-membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur where it is a five-membered ring.
Examples of heterocyclyls include thiazoylyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. For example, preferred heterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino, and more preferably, piperidyl.
Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl.
xe2x80x9cAcylxe2x80x9d refers to a carbonyl moiety attached to either a hydrogen atom (i.e., a formyl group) or to an optionally substituted alkyl or alkenyl chain, or heterocyclyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo, and iodo, and preferably chloro or bromo as a substituent.
xe2x80x9cAlkanediylxe2x80x9d or xe2x80x9calkylenexe2x80x9d represents straight or branched chain optionally substituted bivalent alkane radicals such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene.
xe2x80x9cAlkenediylxe2x80x9d represents, analogous to the above, straight or branched chain optionally substituted bivalent alkene radicals such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, the carbon atom linking a nitrogen preferably should not be unsaturated.
xe2x80x9cAroylxe2x80x9d refers to a carbonyl moiety attached to an optionally substituted aryl or heteroaryl group, wherein aryl and heteroaryl have the definitions provided above. In particular, benzoyl is phenylcarbonyl.
As defined herein, two radicals, together with the atom(s) to which they are attached may form an optionally substituted 4- to 7-, 5- to 7-, or a 5- to 6-membered ring carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic. Said rings may be as defined above in the Summary of the Invention section. Particular examples of such rings are as follows in the next section.
xe2x80x9cPharmaceutically acceptable salts, esters, and amidesxe2x80x9d include carboxylate salts (e.g., C1-8alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic) amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C1-6alkyl amines and secondary di (C1-6alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C1-3alkyl primary amines, and di(C1-2alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C1-7alkyl, C5-7cycloalkyl, phenyl, and phenyl(C1-6)alkyl esters. Preferred esters include methyl esters.
xe2x80x9cPatientxe2x80x9d or xe2x80x9csubjectxe2x80x9d includes mammals such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient or subject is a human.
xe2x80x9cCompositionxe2x80x9d includes a product comprising the specified ingredients in the specified amounts as well as any product which results directly or indirectly from combinations of the specified ingredients in the specified amounts.
xe2x80x9cTherapeutically effective amountxe2x80x9d or xe2x80x9ceffective amountxe2x80x9d means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
Concerning the various radicals in this disclosure and in the claims, three general remarks are made. The first remark concerns valency. As with all hydrocarbon radicals, whether saturated, unsaturated or aromatic, and whether or not cyclic, straight chain, or branched, and also similarly with all heterocyclic radicals, each radical includes substituted radicals of that type and monovalent, bivalent, and multivalent radicals as indicated by the context of the claims. The context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms removed (multivalent). An example of a bivalent radical linking two parts of the molecule is G in formula (I) which links two rings.
Second, radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments. Hydrocarbyls include monovalent radicals containing carbon and hydrogen such as alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromatic or unsaturated), as well as corresponding divalent radicals such as alkylene, alkenylene, phenylene, and so on. Heterocarbyls include monovalent and divalent radicals containing carbon, hydrogen, and at least one heteroatom. Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl, and so on. Using xe2x80x9calkylxe2x80x9d as an example, xe2x80x9calkylxe2x80x9d should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (chlorofluoro), or different (chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, perfluoromethyl, and 3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and 2-aminopropyl), nitroalkyl, alkylalkyl, and so on. A di(C1-6alkyl)amino group includes independently selected alkyl groups, to form, for example, methylpropylamino and isopropylmethylamino, in addition dialkylamino groups having two of the same alkyl group such as dimethyl amino or diethylamino.
Third, only stable compounds are intended. For example, where there is an NRxe2x80x2Rxe2x80x3 group, and R can be an alkenyl group, the double bond is at least one carbon removed from the nitrogen to avoid enamine formation. Similarly, where a dashed line is an optional sp2 bond, if it is absent, the appropriate hydrogen atom(s) is(are) included.
Preferred substitutions for Ar include methyl, methoxy, fluoromethyl, difluoromethyl, perfluoromethyl (trifluoromethyl), 1-fluoroethyl, 2-fluoroethyl, ethoxy, fluoro, chloro, and bromo, and particularly methyl, bromo, chloro, perfluoromethyl, perfluoromethoxy, methoxy, and fluoro. Preferred substitution patterns for Ar are 4-substituted or 3,4-disubstituted phenyl. Compounds of the invention are further described in the next section.
B. Compounds
The invention features compounds of formula (I) as described in the Summary section.
Preferred compounds include those wherein:
(a) one of S, T, Y, and Z is nitrogen;
(b) S and T are CR3 and CR2, respectively;
(c) S, T, Y, and Z are CR3, CR2, CR20, and CR21, respectively;
(d) (1)Z is N, Y is N, S is CR3, and T is CR2; or (2) S is N, T is N, Y is CR20, and Z is CR21;
(e) R2 is hydrogen, halogen, C1-5alkoxy, cyano, ReRfN, or a 5-6 membered heterocyclyl;
(f) R3 is hydrogen, halogen, C1-5alkoxy, C1-5alkyl, cyano, R17OCxe2x95x90O, or RgRhN, where Rg and Rh are H or C1-5alkyl, or are taken together to form a 5-6 membered heterocyclyl;
(g) each of R2 and R3 is independently selected from hydrogen, halogen, and a 5-6 membered heterocyclyl;
(h) R5 and R6 are independently selected from hydrogen and C1-3alkyl;
(i) one of R5 and R6 is H;
(j) R5 and R6 are each H;
(k) one of R7 and R8 is H and the other is 5-7 membered carbocyclyl or heterocyclyl;
(l) R7 and R8 are taken together to form an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring;
(m) R7 and R8 are taken together to form a six-membered heterocyclyl;
(n) R7 and R8 taken together form a 5-7 membered heterocyclyl optionally N-substituted with Rt(Cxe2x95x90O)xe2x80x94, RtSO2xe2x80x94, or NHRu(Cxe2x95x90O)xe2x80x94 wherein Rt is C1-6alkyl, phenyl, or C2-5heterocyclyl and Ru is H, C1-6alkyl, phenyl, or C2-5heterocyclyl;
(o) each of Rc, Re, Rm, and Ro is independently selected from hydrogen, C1-5alkyl, C2-8acyl, (C1-5alkyl)OCxe2x95x90O, and the respective RRNCxe2x95x90O, RSO, RSQ2, and RRNSO2 groups;
(p) each of Rc, Rd, Rg, Rh, Ro, Rf, and Rp is independently selected from hydrogen and C1-5alkyl; or, independently, Re and Rf, Rg and Rh, or Ro and Rp taken together form an optionally substituted 4- to 7-membered carbocyclic or heterocyclic ring;
(q) Re and Rf taken together are morpholinyl, piperidinyl, or pyrrolidinyl;
(r) each of R43, R44, R45, R46, R47, R48, Ri, Rj, Rkand Rl independently is hydrogen or C1-5alkyl;
(s) each of R9, R11, R14, R15, R16 and R17 is independently C1-5alkyl;
(t) Rg is C1-5alkyl, C2-8acyl, R9OCxe2x95x90O, R18R19NCxe2x95x90O, R9SO, R9SO2, or R18R19NSO2; and Rh is H or C1-5alkyl; alternatively, Rg and Rh can be taken together to form an optionally substituted 5- to 6-membered heterocyclyl;
(u) Rg and Rh are each C1-3alkyl;
(v) R18 and R19 independently are hydrogen or C1-5alkyl;
(w) n is 0 or 1; or n is 1;
(x) G is C3-4alkanediyl, optionally substituted with hydroxy, halogen, [(L)-C1-5alkylene]amino, or (L)-C1-5alkyloxy;
(y) G is C3alkanediyl, optionally substituted with hydroxy;
(z) R20 and R21 are independently selected from hydrogen, halogen, C1-5alkoxy, C1-5alkyl, cyano, nitro, 4-7 membered heterocyclyl, and RoRpN or RcRdN, respectively;
(aa) R20 and R21 are independently selected from hydrogen, halogen, 5- to 6-membered heterocyclyl, and RoRpN or RcRdN, respectively;
(bb) Ar represents a monocyclic ring, optionally substituted with 1 to 2 substituents selected from halogen, C1-5alkyl, cyano, nitro, R22R23N, C1-3haloalkyl, and C1-3haloalkoxy;
(cc) Ar is a six-membered aromatic ring monosubstituted at the 4-position with halogen, methyl, CF3, or OCF3, or disubstituted at the 3- and 4-positions with substituents independently selected from halogen, CF3, methyl, and OCF3;
(dd) each of R22, R23, and R24 is independently hydrogen or C1-5alkyl;
(ee) R25 and R26 independently are hydrogen or C1-5alkyl, or, alternatively, R25 and R26 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
(ff) R25 and R26 independently are hydrogen or C1-5alkyl;
(gg) Q is NR33 or S;
(hh) Q is NR33, R33 is H or C2-5heterocyclyl, and R32 is H, C1-5alkyl, C1-5hydroxyalkyl, xe2x80x94(Cxe2x95x90O)NRvRx, CHO, or C1-6alkoxycarbonyl, wherein each of Rv and Rx is independently selected from H, C1-5hydroxyalkyl, (C1-5heterocyclyl)-C1-5alkylene, and C1-5aminoalkylene;
(ii) wherein Q is S and R33 is NR36R37(Cxe2x95x90O)xe2x80x94 where each of R36 and R37 are independently selected from hydrogen and C1-5alkyl;
(jj) R35 is selected from hydrogen and C1-5alkyl; R36 and R37 are each independently selected from hydrogen, C1-5alkyl, or, alternatively, R36 and R37 can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring;
(kk) Y is nitrogen or R20C; Z is nitrogen or R21C; T is nitrogen or R2C; S is nitrogen or R3C; provided between 0 and 2 of S, T, Y, and Z are nitrogen; for example 1 of them is N;
(ll) R2 is hydrogen, halogen, hydroxy, C1-5alkoxy, C1-5alkyl, 5- to 6-membered heterocyclyl, or ReRfN;
(mm) R3 is hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5alkyl, 5- to 6-membered heterocyclyl, or RgRhN;
(nn) R7 and R8 independently are taken together to form an optionally substituted 5- to 7-membered unsaturated heterocyclic ring;
(oo) each of Ra, Re, Rm, and Ro is independently selected from hydrogen, C1-5alkyl, C2-8acyl, (C1-5alkyl)OCxe2x95x90O, and the respective RRNCxe2x95x90O, RSO, RSO2, and RRNSO2 groups;
(pp) each of Rb, Rf, Rn, and Rp, is independently selected from hydrogen and C1-5alkyl; each of R9, R11, R14, R15, R16, R17, R40 R41 and R42 is independently C1-5alkyl; and each of Rc, Rd, Ri, Rj, R43, R44, R45, R46, R47, Rkand Rl are independently are hydrogen or C1-5alkyl;
(qq) Rg is hydrogen, or C1-5alkyl, C2-8acyl, R9OCxe2x95x90O, R18R19NCxe2x95x90O, R9SO, R9SO2, or R18R19NSO2; Rh is hydrogen or C1-5alkyl; alternatively, Rg and Rh can be taken together to form an optionally substituted 4- to 7-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R18 and R19 independently are hydrogen or C1-5alkyl; n is 0 or 1;
(rr) G is C3-4alkenediyl or C3-4alkanediyl, optionally substituted with hydroxy, halogen, C1-5alkyloxy, oxo, hydroximino, CO2Rk, RkRlNCO2, or (L)-C1-5alkoxy; L is amino, mono- or di-C1-5alkylamino, pyrrolidinyl, morpholinyl, piperidinyl homopiperidinyl, or piperazinyl, available ring nitrogens being optionally with C1-5alkyl, benzyl, C2-5 acyl, or C1-5alkyloxycarbonyl;
(ss) R20 and R21 are independently selected from hydrogen, halogen, C1-5alkoxy, C1-5alkyl, cyano, nitro, and RoRpN; alternatively, R3 and R20 or R3 and R21 can be taken together to form an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; and Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with hydrogen, halogen, C1-5alkoxy, C1-5alkyl, cyano, nitro, R22R23N, R24SO2, R24OCxe2x95x90O, R25R26NCxe2x95x90O, CF3, OCF3, SCF3, or C1-5alkylthio; R22 is hydrogen, C1-5alkyl, phenyl, benzyl, phenethyl, C2-5heteroaryl, C2-8acyl, aroyl, R24OCxe2x95x90O, R25R26NCxe2x95x90O, R24SO, R24SO2, or R25R26NSO2; R23 is hydrogen or C1-5alkyl; alternatively, R22 and R23 can be taken together to form an optionally substituted 4- to 7-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R24 is hydrogen or C1-5alkyl; R25 and R26 are independently hydrogen or C1-5alkyl; or, alternatively, R25 and R26 can be taken together to form an optionally substituted 4- to 7-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic;
(tt) R32 is hydrogen, C1-5alkyl, C1-5hydroxyalkyl, CHO, C2-6acyl, C1-6alkoxycarbonyl, or xe2x80x94(Cxe2x95x90O)NRvRx, wherein each of RvRx is independently selected from H, C1-5alkyl, C1-5hydroxyalkyl, C3-8acyloxy, (amino)C1-6alkylene, (C1-5heterocyclyl)C1-5alkylene, or C1-6alkoxycarbonyl; and Q is NR33 or S; R33 represents hydrogen, C1-5alkyl, phenyl, benzyl, (C2-5heterocyclyl)C1-5alkylene, C2-8acyl, aroyl, R35OCxe2x95x90O, R36R37NCxe2x95x90O, R35SO2 and R36R37NSO2; R35 is selected from hydrogen and C1-5alkyl; R36 and R37 are each independently selected from hydrogen and C1-5alkyl;
(uu) one of R5 and R6 is H, R7 and R8 are taken together to form an optionally substituted 6-membered carbocyclic or heterocyclic ring; and Ar represents a monocyclic ring, optionally substituted with 1 to 2 substituents selected from halogen, C1-5alkyl, cyano, nitro, R22R23N, CF3 and OCF3;
(vv) both R5 and R6 are each H, and
(ww) Ar is a six membered ring substituted with halogen, CF3, methyl, halomethyl, or OCF3, at the 3- or 4-position, or disubstituted at the 3- and 4-positions;
(xx) R7 and R8 taken together form pyridinyl, pyrimidinyl, or piperazinyl, optionally N-substituted with xe2x80x94(Cxe2x95x90O)Rt, SO2xe2x80x94Rt, or xe2x80x94(Cxe2x95x90O)NHRu;
(yy) Re and Rf taken together are independently morpholinyl, piperidyl, or pyrrolidinyl, optionally substituted;
(zz) the dashed line adjacent Cxe2x80x94R6 is absent;
(aaa) or combinations of the above.
Specific preferred compounds include those in the Examples below, such as:
1-[1-{2-Hydroxy-3-[4-(1H-indol-3-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol; 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-chloro-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol; 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-chloro-2-methyl-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-methyl-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol; 3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-indole-5-carbonitrile; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-methoxy-1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol; 3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-indole-5-carboxylic acid ethyl ester; 1-[4-(6-Chloro-1H-indol-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol; 1-[1-(3-{4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-2-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-oxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol; 1-[4-(5-Dimethylamino-1-H-pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol; 1-[4-(5-Dimethylamino-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol; 3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-{4-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propan-2-ol; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo [4,3-c]pyridin-1-yl]-3-[4-(7-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol; 1-[4-(6-Fluoro-2-hydroxymethyl-benzo[b]thiophen-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol; 6-Fluoro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carbaldehyde; 6-Fluoro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid methyl ester; 6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylic acid amide; and 6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b]thiophene-2-carboxylic.
Furthermore, preferred compounds include those wherein Ar is selected from 4-trifluoromethylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-chloro-3-methylphenyl and 3,4-dichlorophenyl.
More preferred compounds include those in Examples 4, 9, 13, and 26.
Related Compounds
The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, acids, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms. Related compounds also include compounds of the invention that have been modified to be detectable, e.g., isotopically labelled with 18F for use as a probe in positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. See, e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., (1999) John Wiley and Sons, NY. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
Protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substitute benzyl ethers, and silyl ethers.
Substituted Methyl Ethers
Examples of substituted methyl ethers include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.
Substituted Ethyl Ethers
Examples of substituted ethyl ethers include 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
Substituted Benzyl Ethers
Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,pxe2x80x2-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4xe2x80x2-bromophenacyloxy)phenyldiphenylmethyl, 4,4xe2x80x2, 4xe2x80x3-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4xe2x80x2, 4xe2x80x3-tris(levulinoyloxyphenyl)methyl, 4,4xe2x80x2, 4xe2x80x3-tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-ylmethyl)bis(4 xe2x80x2, 4xe2x80x3-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1xe2x80x2-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
Silyl Ethers
Examples of silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.
Esters
In addition to ethers, a hydroxyl group may be protected as an ester. Examples of esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate(mesitoate).
Carbonates
Examples of carbonate protecting groups include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
Assisted Cleavage
Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate, 4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.
Miscellaneous Esters
Examples of miscellaneous esters include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate), o-(methoxycarbonyl)benzoate, p-P-benzoate, xcex1-naphthoate, nitrate, alkyl N,N,Nxe2x80x2,Nxe2x80x2-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.
Sulfonates
Examples of sulfonates include sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
Protection for the amino group includes carbamates, amides, and special xe2x80x94NH protective groups.
Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, photolytic cleavage carbamates, urea-type derivatives, and miscellaneous carbamates.
Carbamates
Examples of methyl and ethyl carbamates include methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, and 4-methoxyphenacyl.
Substituted Ethyl
Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2xe2x80x2- and 4xe2x80x2-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.
Assisted Cleavage
Examples of assisted cleavage include 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2-(trifluoromethyl)-6-chromonylmethyl.
Photolytic Cleavage
Examples of photolytic cleavage include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl.
Urea-Type Derivatives
Examples of urea-type derivatives include phenothiazinyl-(10)-carbonyl derivative, Nxe2x80x2-p-toluenesulfonylaminocarbonyl, and Nxe2x80x2-phenylaminothiocarbonyl.
Miscellaneous Carbamates
Examples of miscellaneous carbamates include t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p-(pxe2x80x2-methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and 2,4,6-trimethylbenzyl.
Examples of Amides Include
Amides
N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, N-p-phenylbenzoyl.
Assisted Cleavage
N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (Nxe2x80x2-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.
Cyclic Imide Derivatives
N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.
Examples of special NH protective groups include
N-Alkyl and N-Aryl Amines
N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine Nxe2x80x2-oxide.
Imine Derivatives
N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, and N-(Nxe2x80x2,Nxe2x80x2-dimethylaminomethylene).
Acyclic Acetals and Ketals
Examples of acyclic acetals and ketals include dimethyl, bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.
Cyclic Acetals and Ketals
Examples of cyclic acetals and ketals include 1,3-dioxanes, 5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane, 5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane, O,Oxe2x80x2-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.
Acyclic Dithio Acetals and Ketals
Examples of acyclic dithio acetals and ketals include S,Sxe2x80x2-dimethyl, S,Sxe2x80x2-diethyl, S,Sxe2x80x2-dipropyl, S,Sxe2x80x2-dibutyl, S,Sxe2x80x2-dipentyl, S,Sxe2x80x2-diphenyl, S,Sxe2x80x2-dibenzyl and S,Sxe2x80x2-diacetyl.
Cyclic Dithio Acetals and Ketals
Examples of cyclic dithio acetals and ketals include 1,3-dithiane, 1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.
Acyclic Monothio Acetals and Ketals
Examples of acyclic monothio acetals and ketals include O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or xe2x80x94S-phenyl and O-methyl-S-2-(methylthio)ethyl.
Cyclic Monothio Acetals and Ketals
Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.
O-Substituted Cyanohydrins
Examples of O-substituted cyanohydrins include O-acetyl, O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
Substituted Hydrazones
Examples of substituted hydrazones include N,N-dimethyl and 2,4-dinitrophenyl.
Oxime Derivatives
Examples of oxime derivatives include O-methyl, O-benzyl and O-phenylthiomethyl.
Imines
Substituted Methylene Derivatives, Cyclic Derivatives
Examples of substituted methylene and cyclic derivatives include oxazolidines, 1-methyl-2-(1xe2x80x2-hydroxyalkyl)imidazoles, N,Nxe2x80x2-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles, diethylamine adducts, and methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.
Esters
Substituted Methyl Esters
Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, xcex1-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl.
2-Substituted Ethyl Esters
Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl, 2-haloethyl, xcfx89-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2xe2x80x2-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, xcex1-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and benzyl.
Substituted Benzyl Esters
Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, 4-picolyl and p-P-benzyl.
Silyl Esters
Examples of silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl and di-t-butylmethylsilyl.
Activated Esters
Examples of activated esters include thiols.
Miscellaneous Derivatives
Examples of miscellaneous derivatives include oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and pentaaminocobalt(III) complex.
Stannyl Esters
Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl.
Amides
Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.
Hydrazides
Examples of hydrazides include N-phenyl and N,Nxe2x80x2-diisopropyl hydrazides.
C. Synthesis
The compounds of the present invention may be prepared by conventional synthetic organic chemistry and by matrix or combinatorial methods according to Schemes 1 to 12 below, and Examples 1 to 13. Those of ordinary skill in the art will be able to modify and adapt the guidance provided herein to make the disclosed compounds. 
D. Formulation and Administration
The present compounds inhibit the proteolytic activity of human cathepsin S and therefore are useful as a medicine especially in methods for treating patients suffering from disorders or conditions which are modulated or regulated by the inhibition of cathepsin S activity.
The invention features a method for treating a subject with a condition mediated by cathepsin S, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. The invention also provides a method for inhibiting cathepsin S activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. A third method is a method for treating an autoimmune disease, or inhibiting the progression of an autoimmune disease, in a subject, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a disclosed compound. The autoimmune disease can be, for example, lupus, rheumatoid arthritis, or preferably, asthma. The invention also provides a method for treating or inhibiting the progression of tissue transplant rejection in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. The administration step can occur before, during, and/or after a tissue transplant procedure.
In view of their inhibitory effect on the proteolytic activity of human cathepsin S the compounds of the present invention may be formulated into various pharmaceutical forms for administration purposes. To prepare these pharmaceutical compositions, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is intimately mixed with a pharmaceutically acceptable carrier.
A carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration or parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. These include water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. In view of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are generally employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Such additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid addition salts of the compounds of formula I, due to their increased water solubility over the corresponding base form, are more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Pharmaceutically acceptable acid addition salts include the therapeutically active non-toxic acid addition salt forms which the disclosed compounds are able to form. The latter can conveniently be obtained by treating the base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, palmoic and the like acids. The term addition salt also comprises the solvates which the disclosed componds, as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like. Conversely the salt form can be converted by treatment with alkali into the free base form.
Stereoisomeric forms defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the (R)- or (S)-configuration; substituents on bivalent cyclic saturated radicals may have either the cis- or trans-configuration. The invention encompasses stereochemically isomeric forms including diastereoisomers, as well as mixtures thereof in any proportion of the disclosed compounds. The disclosed compounds may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above and following formulae are intended to be included within the scope of the present invention.
Those of skill in the treatment of disorders or conditions mediated by the cathepsin S enzyme could easily determine the effective daily amount from the test results presented hereinafter and other information. In general it is contemplated that a therapeutically effective dose would be from 0.001 mg/kg to 5 mg/kg body weight, more preferably from 0.01 mg/kg to 0.5 mg/kg body weight. It may be appropriate to administer the therapeutically effective dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.05 mg to 250 mg, and in particular 0.5 to 50 mg of active ingredient per unit dosage form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg, and 35 mg dosage forms. Compounds of the invention may also be prepared in time-release or subcutaneous or transdermal patch formulations. Disclosed compound may also be formulated as a spray or other topical or inhalable formulations.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the patient may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned herein are therefore only guidelines.
The next section includes detailed information relating to the preparation, characterization, and use of the disclosed compounds.